11β LONG-CHAIN SUBSTITUTED ESTRATRIENES, METHOD FOR THEIR PRODUCTION, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 11β LONG-CHAIN SUBSTITUTED ESTATRIENES, AND THEIR USE FOR PRODUCING MEDICAMENTS

ABSTRACT

This invention describes a 11β-long-chain-substituted estratriene of general formula (I), in which R 11  is a long-chain radical that has a nitrogen atom and optionally a sulfur atom, which in addition can be functionalized in the terminal position with a perfluoroalkyl group or an optionally substituted arly radical. The compound can have antiestrogenic or tissue-selective estrogenic properties and be suitable for the production of pharmaceutical agents.

This application is a 371 of PCT/EP00/05969 filed Jun. 26, 2000.

This invention relates to 11β-long-chain-substituted estratrienes ofgeneral formula I

in which

R³ means a hydrogen atom, a hydrocarbon radical with up to 8 carbonatoms or a radical of partial formula R³′—C(O)—, in which R³′ means ahydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or aphenyl radical,

R¹¹ means a radical of formula —A—B—Z—R²⁰, in which

A stands for a direct bond, and

B stands for a straight-chain or branched-chain alkylene, alkenylene oralkinylene group with 4, 5 or 6 carbon atoms, or

A stands for a phenylene radical, and

B stands for a methylene, ethylene, propylene or trimethylene group, or

A stands for a phenylenoxy radical, whereby the latter is bonded via acarbon atom to the 11-carbon atom of the steroid, and

B stands for an ethylene group, and

Z stands for —NR²¹— and R²¹ stands for a C₁-C₃ alkyl group,

whereby R²⁰ means

a hydrogen atom,

a straight-chain or branched-chain alkyl, alkenyl or alkinyl group withup to 10 carbon atoms, whereby if A is a direct bond, R²⁰ and R²¹ do notboth simultaneously mean methyl, however, and, if A is a phenylenoxyradical, R²⁰ and R²¹ do not both simultaneously mean methyl or ethyl ineach case, and if A is a phenylenoxy radical and B means an ethylenegroup, OR^(17b) should not be a hydroxy group and R^(17a) should not bea C₁₋₄ alkyl group, and R³ should not be a hydrogen atom,

or one of groupings

—D—C_(n)F_(2n+1), whereby D is a straight-chain or branched-chainalkylene, alkenylene or alkinylene group with up to 8 carbon atoms and nis an integer from 1 to 8, D-aryl, whereby D has the already indicatedmeaning, and aryl stands for a phenyl, 1- or 2-naphthyl radical or aheteroaryl radical that is optionally substituted in one or two places,

—L—CH═CF—C_(p)F_(2p+1), whereby L is a straight-chain or branched-chainalkylene, alkenylene or alkinylene group with up to 7 carbon atoms and pis an integer from 1 to 7,

whereby in the three cases above in D or L, a methylene group can bereplaced by a sulfur atom, a sulfone group or a sulfoxide group,

—D—O—(CH₂)_(q)-aryl, whereby D and aryl have the already indicatedmeanings, and q is 0, 1, 2 or 3,

—D—O—(CH₂)_(r)—C_(n)F_(2n+1), whereby D and n have the already indicatedmeanings, and r stands for an integer from 1 to 5,

whereby in addition in all relevant cases above, R²¹ together with Dwith the inclusion of the nitrogen atom can then form a pyrrolidine ringthat is substituted in 2- or 3-position, or

if A is a direct bond or a phenylene radical, R²⁰ and R²¹ with thenitrogen atom to which they are bonded form a saturated or unsaturatedheterocyclic compound with 5 or 6 chain links, which optionally containsone or two additional heteroatoms, selected from nitrogen, oxygen andsulfur, and optionally is substituted,

whereby if A is a phenylene radical and B is a trimethylene radical, R²¹and R²⁰ do not form a methyl or ethyl group, or, together with thenitrogen atom to which they are bonded, do not form a pyrrolidine or and

R^(17aα)in α- or β-position means a hydrogen atom, a C₁₋₅ alkyl, a C₂₋₅alkenyl or a C₂₋₅ alkinyl group or a trifluoromethyl group, or togetherwith the radical OR^(17b) means a keto-oxygen atom, and

R^(17b) means a hydrogen atom or a radical of partial formulaR¹⁷′—C(O)—, in which R¹⁷′ means a hydrogen atom or a hydrocarbon radicalwith up to 8 carbon atoms.

As R³, the substituted estratrienes according to the inventionpreferably have a hydrogen atom. The hydroxy group, however, can also beetherified with a straight-chain or branched-chain, saturated orunsaturated hydrocarbon radical with up to 8 carbon atoms, such as,e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical oresterified with an acyl radical R³′—C(O)—, in which R³′ is a hydrogenatom or a hydrocarbon radical with up to 8 carbon atoms or a phenylradical.

A hydrogen atom or a radical of partial formula R¹⁷′—C(O)— can stand forsubstituents R^(17b), in which R¹⁷′ is a hydrogen atom or a hydrocarbonradical with up to 8 carbon atoms. A hydrogen atom is preferred forR^(17b). The hydrocarbon radical can have the meaning of, for example, amethyl, ethyl, propyl, isopropyl; butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, heptyl, hexyl or octyl radical. In addition, thesubstituent —OR^(17b) can be in α- or β-position. The β-position ispreferred.

R^(17b) can mean a hydrogen atom, a straight-chain or branched C₁₋₅alkyl radical, such as, for example, a methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl radical, astraight-chain or branched C₂₋₅ alkenyl radical, such as, for example,an ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-ethyl-ethenyl, 2-ethylethenyl, 1-methyl(1-propenyl),1-methyl(2-propenyl) radical, or a straight-chain or branched C₂₋₅alkinyl radical, such as, for example, an ethinyl, 1-propinyl,2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, 3-methyl (1-butinyl)-,1-methyl (3-butinyl) radical and a trifluoromethyl radical.

R^(17b) preferably means a hydrogen atom, a C₂₋₃ alkenyl radical, a C₂₋₃alkinyl radical or a trifluoromethyl group.

R^(17a) especially preferably means a hydrogen atom, a methyl group, anethenyl radical, an ethinyl radical or a trifluoromethyl group.

In addition, the radical R^(17a) can be in α- or β-position. Theα-position is preferred for R^(17a).

Another meaning for R^(17b) together with OR^(17a) is a keto-oxygenatom. This meaning is to be preferred before any other substitution in17-position.

In the compounds of general formula I according to the invention, Astands for a direct bond, a phenylene or phenylenoxy radical, wherebythe latter is connected via one of its carbon atoms to carbon atom 11 ofthe steroid skeleton.

An aryl radical that optionally can be substituted is a phenyl, 1- or2-naphthyl radical in terms of this invention; the phenyl radical ispreferred. Unless expressly indicated otherwise, aryl also alwaysincludes a heteroaryl radical. Examples of a heteroaryl radical are the2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or5-pyrimidinyl or the 3- or 4-pyridazinyl radical.

If R²⁰ and R²¹ with the nitrogen atom, to which they are bonded, containa saturated or unsaturated heterocycle with 5 or 6 chain links, whichoptionally contains one or two additional heteroatoms that are selectedfrom nitrogen, oxygen and sulfur, this is especially a pyrrolidine,piperidine, morpholine or piperazine ring

As substituents for the aryl, heteroaryl, aralkyl and heteroarylalkylradicals, for example, a methyl-, ethyl-, propyl-, trifluoromethyl-,pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-,cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-,mono(C₁₋₈ alkyl)- or di(C₁₋₈ alkyl)amino, whereby both alkyl groups areidentical or different, di(aralkyl)amino, whereby both aralkyl groupsare identical or different (for aralkyl, see above at R²⁰ and R³¹) orthe 1-methoxyacetylamino radical can be mentioned.

The sulfur atom in the side chain can be present as a single sulfurbridge (sulfide), as sulfone or sulfoxide.

As specific side chains,

—(CH₂)₅N(CH₃)—(CH₂)₃—S—(CH₂)₃C₂F₅

—(CH₂)₅NH—(CH₂)₃—S—(CH₂)₃C₂F₅

—(CH₂)₅N(CH₃)—(CH₂)₃—S—CH₂-2-Pyridyl

—(CH₂)₅N(CH₃)—(CH₂)₃—SO—CH₂-2-Pyridyl

—(CH₂)₅N(CH₃)—(CH₂)₃—S—CH₂-p-CF₃-Phenyl

—(CH₂)₅N(CH₃)—(CH₂)₃—SO—CH₂-p-CF₃-Phenyl

—(CH₂)₅-[2-Pyrrolidin-1-yl]—CH₂—S-p-CF₃-Phenyl

—(CH₂)₅-[2-Pyrrolidin-1-yl]—CH₂—SO-p-CF₃-Phenyl

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—S—(CH₂)₃C₂F₅

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—SO—(CH₂)₃C₂F₅

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—S—CH₂-2-Pyridyl

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—SO—CH₂—2-Pyridyl

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—S—CH₂-p-CF₃-Phenyl

p-Phenylen-(CH₂)₂—N(CH₃)—(CH₂)₃—SO—CH₂-p-CF₃-Phenyl

—(CH₂)₅N(CH₃)(CH₂)₃C₂F₅

—(CH₂)₅N(CH₃)(CH₂)₆C₂F₅

—(CH₂)₅N(CH₃)(CH₂)₇C₂F₅

—(CH₂)₅N(CH₃)(CH₂)₈C₂F₅

—(CH₂)₆N(CH₃)(CH₂)₆C₂F₅

—(CH₂)₆N(CH₃)(CH₂)₇C₂F₅

—(CH₂)₆N(CH₃)(CH₂)₈C₂F₅

—(CH₂)₅N(CH₃)(CH₂)₂C₄F₉

—(CH₂)₅N(CH₃)(CH₂)₃C₆F₁₃

—(CH₂)₅N(CH₃)(CH₂)₃C₈F₁₇

—(CH₂)₅N(CH₃)(CH₂)₆C₄F₉

—(CH₂)₅N(CH₃)(CH₂)₆C₆F₁₃

—(CH₂)₅N(CH₃)(CH₂)₆C₈F₁₇

—(CH₂)₅N(CH₃)H

—(CH₂)₅N(CH₃)(CH₂)₉H

—(CH₂)₅N(CH₃)CH₂CH═CF—C₂F₅

—(CH₂)₅N(CH₃)CH₂CH═CF—C₃F₇

—(CH₂)₅N(CH₃)CH₂CH═CF—C₅F₁₁

—(CH₂)₅N(CH₃)CH₂CH═CF—C₇F₁₅

—(CH₂)₅-1-Pyrrolidinyl

—(CH₂)₅N(CH₃)(CH₂)₃OPhenyl

—(CH₂)₅N(CH₃)(CH₂)₃OBenzyl

—(CH₂)₅N(CH₃)(CH₂)₃O(CH₂)₃C₂F₅

—(CH₂)₅N(CH₃)(CH₂)₃CH(CH₃)₂

—(CH₂)₅N(CH₃)(CH₂)₃-Pyridyl

—(CH₂)₅N(CH₃)(CH₂)₃-Phenyl

—(CH₂)₅N(CH₃)(CH₂)₂-p-Tolyl

—(CH₂)₅N(CH₃)(CH₂)₂-p-Ethoxyphenyl

—(CH₂)₅N(CH₃)(CH₂)₃-p-Tolyl⁻

—(CH₂)₅N(CH₃)(CH₂)₃-p-Chlorphenyl

—(CH₂)₅N(CH₃)(CH₂)₃—O—CH₂-Phenyl

—(CH₂)₅N(CH₃)(CH₂)₂—O-p-Br-Phenyl

—(CH₂)₅N(CH₃)(CH₂)₂—O-p-CF₃-Phenyl can be mentioned.

[Key:]

—(CH₂)₅-[2-Pyrrolidin-1-yl]- . . . =(CH₂)₅-[2-pyrrolidine-1-yl]- . . .p-Phenylen- . . . =p-phenylene- . . .

This invention relates to the following compounds, i.a.:

11β-[5-(Methyl(3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

11β-(5-{3-[(4;4,5,5,5-pentafluoropentyl)sulfanyl]propyl-amino}pentyl)estra-1,3,5(10)-triene-3,17β-diol

11β-[5-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

11β-[5-(methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

11β-[5-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

11β-[5-(methyl{3-[4-(trifluoromethyl)benzylsulfinyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfanyl-methyl}pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfinyl-methyl}pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)ethyl]phenyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}-amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{4-[2-(methyl{3-[4-(trifluoromethyl)benzylsulfinyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(8,8,9,9,9-pentafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5[methyl-nonyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{6-[methyl-(8,8,9,9,9-pentafluoro-nonyl)amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{6-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-triene-3,17β-diol

11β-(5-pyrrolidin-1-yl-pentyl)-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-undecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{6-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(3,4,4,5,5,6,6,7,7,8,8,8-dodecafluoro-oct-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(3-phenoxy-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[(3-benzyloxy-propyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentyloxy)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(2-p-tolyl-ethyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-(5-{[2-(4-ethoxy-phenyl)-ethyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(3-phenyl-propyl)-amino)-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(3-pyridin-3-yl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(3-p-tolyl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

11β-(5-{[3-(4-chloro-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol

11β-(5-{[3-(4-ethoxy-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol

11β-{5-[methyl-(4-methyl-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol

In addition to these compounds of general formula I, this invention alsorelates to their physiologically compatible addition salts with organicand inorganic acids, pharmaceutical preparations that contain thesecompounds of general formula I inclusive of the addition salts, as wellas their use for the production of pharmaceutical agents.

Inorganic and organic acids, as are known to one skilled in the art forthe formation of physiologically compatible salts, are suitable for theformation of acid addition salts. As addition salts with acids,especially hydrochlorides, hydrobromides, acetates, citrates, oxalates,tartrates and methanesulfonates can be cited.

The compounds of general formula I represent compounds with strongantiestrogenic action and with surprising possible oral uses.

The compounds according to the invention are either pure antiestrogensor so-called partial antagonists, i.e., antiestrogens with partialestrogenic action such as tamoxifen or raloxifen. In contrast to thetamoxifen, their agonistic, estrogenic action is expressed in atissue-selective manner in the case of partial antagonists of generalformula I. In particular, the agonistic action occurs in bone, in thecardiovascular system and in the central nervous system. In particular,no action or only slightly agonistic action occurs in the uterus.

Compounds with antiestrogenic properties, i.e., substances withinhibiting actions compared to estrogens, have already been describedextensively.

Estratrienes that carry a β-position substituent in 11-position and thatalso have, i.a., antiestrogenic action, are known from, for example, thefollowing patent applications:

WO 98/28324, EP-A 0 850 647, EP-A 0 629 635, WO 93/13123, EP-A 0 558416, EP-A 0 471 612, EP-A 0 384 842, EP-B 0 097 572, WO/99 25725.

In addition, the steroid derivatives that are known from EP 0 138 504 B1can be mentioned. The7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17β-diolis currently under clinical development for hormone-dependent tumors(breast cancer).

Pharmaceutical compositions that contain sex steroid inhibitors and thathave a steroidal skeleton that has a 7α-side chain in the case of thesimultaneous presence of at least one other substituent in 14-, 15- or16-position are the subject matter of EP-A 0 376 576.

Antiestrogenically active estratrienes that can carry an 11β-fluorineatom and carry an a-position side chain in 7-position, which has anamino group and a sulfur group and that is functionalized in theterminal position, are described in WO 98/07740.

The compounds according to the invention are compounds with strongerantiestrogenic action after peroral administration.

The antiuterus growth test in infant rats, s.c. and p.o. (test onantiestrogenic action in-vivo) confirms the antiestrogenic action of thecompounds according to the invention. The test is performed as describedbelow:

Uterus Growth Test in Infant Rats (Antiestrogenic Action) Principle ofthe Method

In rodents, the uterus reacts to the administration of estrogens with anincrease in weight (both proliferation and water retention). This growthcan be inhibited in a dose-dependent manner by simultaneousadministration of compounds that have an antiestrogenic action.

Execution of the Test

Animals:

Infant female rats weighing 35-45 g at the beginning of the test, 5-6animals per dose.

Formulation and Administration of the Substances:

For the p.o. administration, the substances are dissolved in 1 partethanol (E) and made up with 9 parts peanut oil (EÖ).

Test Batch

The young rats just dropped by the mothers are delivered for acclimationone day before the beginning of treatment and immediately supplied withfood—right in the cage. The treatment is then carried out once dailyover 3 days in combination with 0.5 μg of estradiol benzoate (EB). EB isalways administered subcutaneously (s.c.), while the test substance isadministered p.o. (perorally). 24 hours after the last administration,the animals are weighed, killed and the uteri are removed. The moistweight (less contents) is determined from the prepared uteri.

Controls

Negative control: Vehicle (E/Ë), 0.2 ml/animal/day

Positive control: 0.5 μg of EB/0.1 ml/animal/day

Evaluation

The average values with standard deviation (X+SD) and the significanceof the differences in the control group (EB) in the Dunnett Test(p<0.05) are determined for each group from the relative organ weights(mg/100 g of body weight). The calculation of the inhibition (in %)compared to the EB-control is carried out with a program. The relativeactions of the test substances are determined by co-variance analysisand regression analysis.

As pure antiestrogens for the purposes of this invention, thosecompounds of general formula I that show no action or, in the best case,only slightly agonistic action, in the in-vitro test on estrogenicaction can be considered.

By means of the method described below, the estrogenic effect of thecompounds according to the invention on the bones can be determined. Inthe case of selectively estrogenically active compounds, protectiveeffects on the bones are observed with comparable dosages, while on theuterus, no stimulation, or in the best case, only slight stimulation, isnoted.

Bone Studies Method

Female rats that are three months old are ovariectomized and treatedonce daily with the test compound immediately after the operation for 28days. The administration is carried out subcutaneously in castoroil/benzyl benzoate or arachis oil/ethanol. The animals are sacrificedon the day after the last administration, and femurs, tibia as well asthe uteri are removed. The uteri are weighed, mounted and worked up forhistological studies. The determination of the bone density is carriedout ex vivo on prepared long bones via pQCT (Quantitative ComputerTomography). The measurements are made at a distance of 5-7 mm from theball of the joint at the distal femur or the proximal tibia.

As an alternative, the action on the bones by measuring out thetrabecular bone surface area of the secondary spongiosa on histologicpreparations of the distal femur or the proximal tibia is noted. Theresult is expressed as the proportion, in percent, of the trabecularbone surface area to the measured total bone surface area (TB/BV). Thebone density that is measured via QCT and the trabecular bone surfacearea that is determined at the histologic section correlate well withone another. A comparison of the two measurement variables is thereforepermissible.

The transition between the pure antiestrogens and the partial agonists,the tissue-selective estrogens, is seamless. Compounds that have aslightly agonistic action can also be used in the indications that arementioned below for pure antiestrogens:

The compounds according to the invention, especially if they are pureantiestrogens, are suitable for treatment of estrogen-dependentdiseases, for example breast cancer (second-line treatment oftamoxifen-resistant breast cancer; for adjuvant treatment of breastcancer instead of tamoxifen), endometrial cancer, prostate cancer,prostatic hyperplasia, anovulatory infertility and melanoma.

In addition, the pure antiestrogens of general formula I can be used ascomponents in the products that are described in EP 346 014 B1, whichcontain an estrogen and a pure antiestrogen, specifically forsimultaneous, sequential or separate use for selective estrogen therapyof peri- or postmenopausal women. The compounds of general formula I,especially if these are pure antiestrogens, can be used together withantigestagens (competitive progesterone antagonists) for the treatmentof hormone-dependent tumors (EP 310 542 A).

Other indications in which the compounds of the general formula can beused are male hair loss, diffuse alopecia, alopecia that is caused bychemotherapy as well as hirsutism (Hye-Sun Oh and Robert C. Smart, Proc.Natl. Acad. Sci. USA, 93 (1996) 12525-12530).

In addition, the compounds of general formula I can be used for theproduction of medications for treating endometriosis and endometrialcarcinomas.

The compounds of general formula I can also be used for the productionof pharmaceutical compositions for male and female birth control (malebirth control: DE-A 195 10 B62.0).

The compounds of general formula I with tissue-selective partialestrogenic action can be used primarily for prophylaxis and treatment ofosteoporosis and for the production of preparations for substitutiontherapy in pre-, peri- and post-menopause (HRT=hormone replacementtherapy) (Black; L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele,A.; Williams; D. C.; Cullinan, C. J.; Bendele, R.; Kauffman, R. F.;Bensch, W. R.; Frolik, C. A.; Termine, J. D. and Bryant, E. U.:Raloxifene [LY 139481 HCl] Prevents Bone Loss and Reduces SerumCholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats;J. Clin. Invest. 93: 63-69, 1994).

The invention also relates to pharmaceutical preparations that containat least one compound of general formula I (or physiologicallycompatible addition salts with organic and inorganic acids of them) andthe use of these compounds for the production of pharmaceutical agents,especially for treating estrogen-dependent diseases and tumors andpharmaceutical agents for hormone replacement therapy (HRT).

The compounds according to the invention and the acid addition salts aresuitable for the production of pharmaceutical compositions andpreparations. As active ingredients, the pharmaceutical compositions orpharmaceutical agents contain one or more of the compounds according tothe invention or their acid addition salts, optionally mixed with otherpharmacologically or pharmaceutically active substances. The productionof the pharmaceutical agents is carried out in a known way, whereby theknown and commonly used pharmaceutical adjuvants and other commonly usedvehicles and diluents can be used.

As such vehicles and adjuvants, for example, those are suitable that arerecommended or indicated in the following bibliographic references asadjuvants for pharmaceutics, cosmetics and related fields: UllmansEncyklopädie der technischen Chemie [Ullman's Encyclopedia of TechnicalChemistry], Volume 4 (1953), pages 1 to 39; Journal of PharmaceuticalSciences, Volume 52 (1963), pages 91B and ff.; issued byCzetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete[Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind. Issue 2,1961, pages 72 and ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fürPharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants forPharmaceutics, Cosmetics and Related Fields] Cantor KG, Aulendorf inWürttemberg 1971.

The compounds can be administered orally or parenterally, for exampleintraperitoneally, intramuscularly, subcutaneously or percutaneously.The compounds can also be implanted in the tissue. The amount of thecompounds to be administered varies within a wide range and can coverany effective amount. Based on the condition to be treated and the typeof administration, the amount of the administered compound can be 0.1-25mg/kg of body weight, preferably 0.5-5 mg/kg of body weight, per day. Inhumans, this corresponds to a daily dose of 5 to 1250 mg. The preferreddaily dosage in humans is 50 to 200 mg. This is true especially fortumor therapy.

For oral administration, capsules, pills, tablets, coated tablets, etc.,are suitable. In addition to the active ingredient, the dosage units cancontain a pharmaceutically compatible vehicle, such as, for example,starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.The individual dosage units for oral administration can contain, forexample, 5 to 500 mg of active ingredient.

To achieve better bio-availability of the active ingredient, thecompounds can also be formulated as cyclodextrin clathrates. For thispurpose, the compounds are reacted with α-, β- or γ-cyclodextrin orderivatives thereof (PCT/EP95/02656).

For parenteral administration, the active ingredients can be dissolvedor suspended in a physiologically compatible diluent. As diluent, veryfrequently oils with or without the addition of a solubilizer, asurfactant, a suspending agent or emulsifier are used. Examples of oilsthat are used are olive oil, peanut oil, cottonseed oil, soybean oil,castor oil and sesame oil.

The compounds of general formula I can also be formulated in the form ofa solution that is determined for oral administration and that inaddition to the active compound of general formula I contains

a) a pharmaceutically compatible oil and/or

b) a pharmaceutically compatible lipophilic surfactant and/or

c) a pharmaceutically compatible hydrophilic surfactant and/or

d) a pharmaceutically compatible water-miscible solvent.

In this respect, reference is made in addition to WO 97/21440.

The compounds can also be used in the form of a depot injection or animplant preparation, which can be formulated in such a way that adelayed release of active ingredient is made possible.

As inert materials, implants can also contain, for example,biodegradable polymers or synthetic silicones such as, for example,silicone gum. In addition, the active ingredients can be embedded in,for example, a patch for percutaneous administration.

For the production of intravaginal systems (e.g., vaginal it rings) orintrauterine systems (e.g., pessaries, spirals) that are loaded withactive compounds of general formula I, various polymers such as, forexample, silicone polymers, ethylene vinyl, acetate, polyethylene orpolypropylene are suitable.

The compounds according to the invention can be produced as describedbelow. The examples below are used for a more detailed explanation ofthe invention. Other compounds of general formula I can be obtained byan analogous procedure using analogous reagents in the data contained inthe examples.

Side chains R¹¹ that do not contain any sulfur groups can be createdanalogously to the corresponding 7α-position side chains of thecompounds that are described in PCT/EP98/08470, whereby the11β-(5-chloropentyl)estra-1,3,5(10)-triene-3,17β-diol that is describedhere in Example 1d or the11β-(5-iodopentyl)estra-1,3,5(10)-triene-3,17β-diol that is described inExample 3a is now to be taken as a starting material.

A thio bridge in the side chain can be oxidized with sodium periodate toform sulfoxide; the sulfones are obtained from the sulfides with aperacid as an oxidizing agent, e.g., m-chloroperbenzoic acid.

The saponification of the ester groupings as well as esterification andetherification of free hydroxy groups is carried out in each caseaccording to established processes of organic chemistry. By observingthe varied reactivity of the esterified and free 3- and 17-hydroxygroups, the 3,17-diesters can be cleaved selectively in 3-position, andthe 3-hydroxy-17-acyloxy compound can then be additionallyfunctionalized specifically in the 3-position; it is equally possible toesterify or to etherify the 3,17-dihydroxy compound selectively only inthe 3-position and then to introduce specifically another radical intothe 17-position as already in the 3-position.

The acid addition salts of the compounds of general formula I can alsobe produced from the compounds of general formula I according tostandard processes.

The examples below are used for a more detailed explanation of theinvention:

EXAMPLE 111β-[5-(Methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

a)11β-[5-(tert-Butyldimethylsilyloxy)pentyl]-3,3-(2,2-dimethyltrimethylenedioxy)-5α-estr-9-ene-5,17β-diol

1.82 g of magnesium in 15 ml of absolute tetrahydrofuran is reactedunder nitrogen with a solution of 21.1 g of1-bromo-5-tert-butyldimethylsilyloxypentane [Tetrahedron Letters 1982,4147-4150] in 40 ml of absolute tetrahydrofuran to form a Grignardreagent. At 0° C., 0.25 g of copper(I) chloride is added, and it isstirred for 15 more minutes, before a solution of 9.36 g of3,3-(2,2-dimethyltrimethylenedioxy)-5,10α-epoxy-5α-estr-9(11)-en-17β-ol[Neef, G. et al., Tetrahedron, (1993), 49, pp. 833-840)] in 40 ml ofabsolute tetrahydrofuran is added in drops, such that the internaltemperature does not exceed 8° C. After the addition is completed, it isstirred for 90 more minutes while being cooled in an ice bath. Forworking-up, the reaction mixture is added to saturated ammonium chloridesolution while being stirred, extracted three times with ethyl acetate,the combined ethyl acetate phases are washed with saturated sodiumchloride solution, dried on sodium sulfate and evaporated to the drystate in a vacuum. Preparative column chromatography on silica gel withhexane/ethyl acetate as an eluant yields 5.02 g of11β-[5-(tert-butyldimethylsilyloxy)pentyl]-3,3-(2,2-dimethyltrimethylenedioxy)-5α-estr-9-ene-5,17β-diolas a foam.

b) 17β-Hydroxy-11β-(5-hydroxypentyl)estra-4,9-dien-3-one

4.96 g of11β-[5-(tert-butyldimethylsilyloxy)pentyl]-3,3-(2,2-dimethyltrimethylenedioxy)-5α-estr-9-ene-5,17β-diolin 36 ml of tetrahydrofuran is stirred under nitrogen with 40 ml ofglacial acetic acid and 20 ml of water for 3 hours at a bath temperatureof 50° C. Then, it is carefully poured onto saturated sodium bicarbonatesolution, extracted three times with ethyl acetate, the combined organicphases are washed with saturated sodium chloride solution, dried onsodium sulfate and evaporated to the dry state in a vacuum. Bypreparative column chromatography on silica gel with hexane/acetone asan eluant, 3.57 g of17β-hydroxy-11β-(5-hydroxyphenyl)estra-4,9-dien-3-one is obtained as afoam.

c) 11β-(5-Hydroxypentyl)-9ξ-estra-1,3,5(10)-triene-3,17β-diol

A solution of 1.08 g of17β-hydroxy-11β-(5-hydroxypentyl)estra-4,9-dien-3-one in 19 ml ofethanol is refluxed with 0.19 g of palladium on activated carbon for 20hours at a bath temperature of 100° C. After cooling, it is filtered onCelite, rewashed with ethyl acetate, the filtrate is evaporated to thedry state and chromatographed on silica gel with hexane/acetone.Recrystallization from methylene chloride results in 0.46 g of11β-(5-hydroxypentyl)-9ξ-estra-1,3,5(10)-triene-3,17β-diol with amelting point of 152° C.

d) 11β-(5-Chloropentyl)estra-1,3,5(10)-triene-3,17β-diol

426 mg of 11β-(5-hydroxypentyl)-9ξ-estra-1,3,5(10)-triene-3,17β-diol issuspended in 7.2 ml of carbon tetrachloride and 2.4 ml of acetonitrile,mixed with 682 mg of triphenyl-phosphine and stirred for 90 minutes atroom temperature. For working-up, the reaction solution is mixed withmethylene chloride, washed with saturated sodium bicarbonate solutionand saturated sodium chloride solution, dried on sodium sulfate, andconcentrated by evaporation in a vacuum. By preparative columnchromatography on silica gel with methylene chloride/ethyl acetate, the9ξ-isomers can be separated. Subsequent crystallization from methylenechloride yields 238 mg of11β-(5-chloropentyl)estra-1,3,5(10)-triene-3,17β-diol with a meltingpoint of 159° C.

e)11β-[5-(Methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl]amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

189 mg of 11β-(5-chloropentyl)estra-1,3,5(10)-triene-3,17β-diol isdissolved in 3 ml of dried dimethylformamide, mixed with 598 mg ofmethyl{3-[(4,4,5,5,5-pentafluoropentyl)-sulfanyl]propyl}amine [DE 196 35525.7] and stirred for 24 hours at 100° C. under nitrogen. After thereaction mixture is cooled, it is diluted with ethyl acetate, washedonce with saturated sodium bicarbonate solution and twice with saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After preparative column chromatography onsilica gel with ethyl acetate/methanol as an eluant, 222 mg of11β-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolis obtained as a foam [a]_(D) ²²=+72.1° (c=0.172 in chloroform).

EXAMPLE 211β-(5-{3-[(4,4,5,5,5-Pentafluoropentyl)sulfanyl]-propylamino}pentyl)estra-1,3,5(10)-triene-3,17β-diol

98 mg of 11β-(5-chloropentyl)estra-1,3,5(10)-triene-3,17β-diol isdissolved in 1.5 ml of dried dimethylformamide, mixed with 3 ml of3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propylamine and stirred for 16hours under nitrogen at a bath temperature of 80° C. After the reactionsolution is cooled, it is diluted with ethyl acetate, washed once withwater and twice with saturated sodium chloride solution, dried on sodiumsulfate and concentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with methylene chloride/methanol with theaddition of ammonia results in 31 mg of11β-(5-{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propylamino}pentyl)-estra-1,3,5(10)-triene-3,17β-diolas a foam.

EXAMPLE 311β-[5-(Methyl{3-[(2-pyridylmethyl)sulfanyl]propyl)-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

a) 11β-(5-Iodopentyl)estra-1,3,5(10)-triene-3,17β-diol

1.46 g of 11β-(5-chloropentyl)estra-1,3,5(10)-triene-3,17β-diol isdissolved in 24 ml of ethylmethylketone, mixed with 1.82 g of sodiumiodide and stirred overnight at a bath temperature of 90° C. Forworking-up, the reaction mixture is added to water, extracted threetimes with ethyl acetate, washed with sodium thiosulfate solution, driedon magnesium sulfate and concentrated by evaporation in a vacuum. 1.86 gof 11β-(5-iodopentyl)estra-1,3,5(10)-triene-3,17β-diol is obtained as acrude product, which is used in the next reaction without furtherpurification.

b)11β-[5-(Methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}amino)-pentyl]estra-1,3,5(10)-triene-3,17β-diol

1.0 g of 11β-(5-iodopentyl)estra-1,3,5(10)-triene-3,17β-diol and 2.47 gof methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}amine are dissolved in 21ml of N-methylpyrrolidone and stirred for 3 hours at 80° C. After thereaction solution is cooled to room temperature, the batch is added tosemi-saturated sodium chloride solution, extracted three times withdiethyl ether, the combined organic phases are washed with water andsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with methylene chloride/methanol as aneluant yields 0.69 g of11β-[5-(methyl{3-[(2-pyridyl-methyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=+62.2° (c=0.519 in chloroform).

EXAMPLE 4 11β-[5-(Methyl{3-[2-pyridylmethyl)sulfinyl]propyl}amino)-pentyl]estra-1,3,5(10)-triene-3,17β-diol

250 mg of11β[5-(methyl{3-[(2-pyridylmethyl)sulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolis dissolved in 8.1 ml of methanol and 0.44 ml of water, mixed with 161mg of sodium metaperiodate and stirred for 16 hours at room temperature.For working-up, the reaction mixture is added to semi-saturated sodiumchloride solution, extracted three times with methylene chloride, thecombined organic phases are dried on magnesium sulfate and concentratedby evaporation in a vacuum. Preparative column chromatography on silicagel with methylene chloride/methanol as an eluant yields 53 mg of11β-[5-(methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolas a foam.

[α]_(D) ²²=+56.9° (c=0.501 in chloroform)

EXAMPLE 511β-[5-(Methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

839 mg of 11β-(5-iodopentyl)estra-1,3,5(10)-triene-3,17β-diol and 1.42 gof methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amine aredissolved in 18 ml of N-methylpyrrolidone and stirred for 90 minutes ata bath temperature of 80° C. After the reaction solution is cooled toroom temperature, the batch is added to semi-saturated sodium chloridesolution, extracted three times with diethyl ether, the combined organicphases are washed with water and saturated sodium chloride solution,dried on magnesium sulfate and concentrated by evaporation in a vacuum.Preparative column chromatography on silica gel with methylenechloride/methanol as an eluant yields 0.94 g of11β-[5-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=+75.0° (c=0.5 in chloroform).

EXAMPLE 611β-[5-(Methyl{3-[4-(trifluoromethyl)benzylsulfinyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol

630 mg of11β-[5-(methyl{3-[4-(trifluoromethyl)benzyl-sulfanyl]propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolis dissolved in 17.4 ml of methanol and 0.95 ml of water, mixed with 329mg of sodium metaperiodate and stirred at room temperature for 16 hours.For working-up, the reaction mixture is added to semi-saturated sodiumchloride solution, extracted three times with methylene chloride, thecombined organic phases are dried on magnesium sulfate and concentratedby evaporation in a vacuum. Preparative column chromatography on silicagel with methylene chloride/methanol as an eluant yields 216 mg of11β-[5-(methyl{3-[4-(trifluoromethyl)benzylsulfinyl]propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=+54.10 (c=0.501 in chloroform).

EXAMPLE 711β-{5-[(2S)-2-{[4-(Trifluoromethyl)phenyl]sulfanylmethyl}-pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol

820 mg of 11β-(5-iodopentyl)estra-1,3,5(l0)-triene-3,17β-diol and 458 mgof (S)-2-{[4-(trifluoromethyl)phenyl]sulfanyl-methyl}pyrrolidine aredissolved in 16 ml of N-methylpyrrolidone and stirred for 3 hours at abath temperature of 90° C. After the reaction solution is cooled to roomtemperature, the batch is added to semi-saturated sodium chloridesolution, extracted three times with ethyl acetate, the combined organicphases are washed three times with water, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with methylene chloride/methanol as aneluant yields 561 mg of11β-{5-[(2S)-2-}[4-(trifluoromethyl)-phenyl]sulfanylmethyl}pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=+33.1° (c=0.5195 in chloroform).

EXAMPLE 811β-{5-[(2S)-2-{[4-(Trifluoromethyl)phenyl]sulfinylmethyl}-pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol

975 mg of 11β-(5-iodopentyl)estra-1,3,5(10)-triene-3,17β-diol and 540 mgof (S)-2-{[4-(trifluoromethyl)phenyl]sulfinyl-methyl}pyrrolidine aredissolved in 19 ml of N-methylpyrrolidone and stirred for 3 hours at abath temperature of 90° C. After the reaction solution is cooled to roomtemperature, the batch is added to semi-saturated sodium chloridesolution, extracted three times with ethyl acetate, the combined organicphases are washed twice with water, dried on magnesium sulfate, andconcentrated by evaporation in a vacuum. Chromatography on silica gelwith methylene chloride/methanol yields 222 mg of11β-{5-[-(2S)-2-{[4-(trifluoromethyl)phenyl]sulfinyl-methyl}pyrrolidine-1-yl]pentyl}-estra-1,3,5(10)-triene-3,17β-diolas a foam. [α]_(D) ²²=+42.6° (c=0.5145 in chloroform).

EXAMPLE 911β-{4-[2-(Methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)ethyl)phenyl}estra-1,3,5(10)-triene-3,17β-diol

a).11β-{4-[2-(tert-Butyldimethylsilyloxy)ethyl]phenyl}-3,3-(2,2-dimethyltrimethylene-dioxy)-5α-estr-9-ene-5,17β-diol

1.94 g of magnesium chips is introduced under nitrogen into 15 ml ofabsolute tetrahydrofuran and mixed with about 2.5 g of1-bromo-4-[2-(tert-butyldimethylsilyloxy)ethyl]benzene in 4 ml ofabsolute tetrahydrofuran as well as a spatula tip full of iodine. Afterthe reaction is started, the residual 22.8 g of1-bromo-4-[2-(tert-butyl-dimethylsilyloxy)ethyl]benzene is added indrops to 36 ml of absolute tetrahydrofuran, and after the addition iscompleted, it is stirred for 1 hour at 80° C. Then, it is cooled to 0°C., mixed with 267 mg of copper(I) chloride and stirred for 30 moreminutes under cold conditions. Then, 10 g of3,3-(2,2-dimethyltrimethylenedioxy)-5,10α-epoxy-5α-estr-9(11)-en-17β-olis added in drops while being cooled in an ice bath in such a way thatthe internal temperature does not exceed +8° C. After 2 hours ofstirring at 0° C., the reaction mixture is added to saturated ammoniumchloride solution, extracted three times with ethyl acetate, washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with hexane/ethyl acetate as an eluantresults in 11.97 g of11β-{4-[2-(tert-butyldimethylsilyloxy)ethyl]phenyl}-3,3-(2,2-dimethyltrimethylenedioxy)-5α-estr-9-ene-5,17β-diol.

b) 17β-Hydroxy-11β-[4-(2-hydroxyethyl)phenyl]estra-4,9-dien-3-one

11.27 g of11β-{4-[2-(tert-butyldimethylsilyloxy)ethyl]-phenyl}-3,3-(2,2-dimethyl-trimethylenedioxy)-5α-estr-9-ene-5,17β-diolis dissolved in 70 ml of tetrahydrofuran, mixed with 86 ml of glacialacetic acid as well as 43 ml of water and stirred for 1 hour at a bathtemperature of 50° C. After the cooling, the reaction solution iscarefully added to ice-cold sodium bicarbonate solution, extracted threetimes with ethyl acetate, washed with saturated sodium chloridesolution, dried on magnesium sulfate and concentrated by evaporation ina vacuum. After preparative column chromatography on silica gel withhexane/acetone as an eluant, 6.73 g of17-hydroxy-11β-[4-(2-hydroxyethyl)phenyl]estra-4,9-dien-3-one isobtained as a foam.

c) 11β-[4-(2-Chloroethyl)phenyl]-17β-hydroxyestra-4,9-dien-3-one

6.32 g of 17β-hydroxy-11β-[4-(2-hydroxyethyl)phenyl]estra-4,9-dien-3-oneis dissolved in 160 ml of methylene chloride, mixed with 7.65 g oftriphenylphosphine and 16.1 ml of perchloro-acetone and stirred for 1hour at room temperature. Then, the reaction mixture is concentrated byevaporation in a vacuum and chromatographed on silica gel withhexane/ethyl acetate as well as methylene chloride/methanol as aneluant. 3.19 g of11β-[4-(2-chloroethyl)phenyl]-17β-hydroxyestra-4,9-dien-3-one isobtained as a foam.

d) 11β-[4-(2Chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol

A solution of 2.94 g of11β-[4-(2-chloroethyl)phenyl]-17β-hydroxyestra-4,9-dien-3-one in 70 mlof ethanol is refluxed with 458 mg of palladium on activated carbon for5 hours at a bath temperature of 100° C. After cooling to roomtemperature, it is filtered on Celite, rewashed with ethanol andconcentrated by, evaporation in a vacuum. Preparative columnchromatography on silica gel with hexane/ethyl acetate as an eluantyields 522 mg of11β-[4-(2-chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol as afoam.

e) 11β-[4-(2-Iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol

312 mg of 11β-[4-(2-chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diolis dissolved in 5 ml of ethylmethylketone, mixed with 341 mg of sodiumiodide and stirred for 16 hours at 90° C. For working-up, the reactionmixture is added to water, extracted three times with ethyl acetate,washed with thiosulfate solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. 382 mg of11β-[4-(2-iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol is obtainedas a crude product, which is used in the next stage without furtherpurification.

f)11β-{4-[2-(Methyl{3-[(4,4,5,5.,5-pentafluoropentyl)sulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

382 mg of 11β-[4-(2-iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-dioland 603 mg ofmethyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propyl}amine aredissolved in 7.5 ml of N-methylpyrrolidone and stirred for 150 minutesat a bath temperature of 90° C. After the reaction solution is cooled toroom temperature, the batch is added to dilute sodium chloride solution,extracted three times with diethyl ether, the combined organic phasesare washed with water and saturated sodium chloride solution, dried onmagnesium sulfate and concentrated by evaporation in a vacuum.Preparative column chromatography on silica gel with methylenechloride/methanol as an eluant yields 180 mg of11β-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)-sulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=−14.4° (c=0.502 in chloroform).

EXAMPLE 1011β-{4-[2-(Methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

205 mg of 11β-[4-(2-chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-dioland 633 mg ofmethyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}amine aredissolved in 5 ml of dimethylformamide, and stirred for 5 hours at abath temperature of 90° C. and for 16 hours at room temperature. Forworking-up, the batch is added to semi-saturated sodium chloridesolution, extracted three times with ethyl acetate, washed twice withwater, dried on magnesium sulfate and concentrated by evaporation in avacuum. The residue is chromatographed on silica gel with methylenechloride/methanol as an eluant. 54 mg of11β-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}-amino)ethyl]-phenyl}estra-1,3,5(10)-triene-3,17β-diolis obtained as a foam, [α]_(D) ²²=−12.9° (c=0.509 in chloroform).

EXAMPLE 1111β-{4-[2-(Methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}amino)-ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

a) 11β-[4-(2-Hydroxyethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol

A solution of 11.7 g of17β-hydroxy-11β-[4-(2-hydroxyethyl)phenyl]estra-4,9-dien-3-one in 295 mlof methanol is stirred with 8.54 g of palladium hydroxide on activatedcarbon (20%) and 2.16 g of magnesium oxide for 5 hours at a bathtemperature of 70° C. After cooling, it is filtered on Celite, washedwith methanol and concentrated by evaporation in a vacuum. The residueis chromatographed on silica gel with hexane/acetone as an eluant. 4.54g of 11β-[4-(2-hydroxyethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol isobtained as a foam, [α]_(D) ²²=−175.5° (c=0.502 in pyridine).

b) 11β-[4-(2-Chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol

4.50 9 of11β-[4-(2-hydroxyethyl)phenyl]estra-1,3,5(l0)-triene-3,17β-diol isdissolved in 114 ml of methylene chloride and mixed in succession with5.45 g of triphenylphosphine and 11.5 ml of perchloroacetone. Then, itis stirred for 90 minutes at room temperature. For working-up, thereaction mixture is concentrated by evaporation in a vacuum andchromatographed on silica gel with methylene chloride/methanol as aneluant. 4.02 g of11β-[4-(2-chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol isobtained as a foam, [α]_(D) ²²=+10.70° (c=0.503 in chloroform).

c) 11β-[4-(2-Iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol

411 mg of 11β-[4-(2-chloroethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diolis dissolved in 6.5 ml of ethylmethylketone, mixed with 449 mg of sodiumiodide and stirred for 16 hours at 90° C. For working-up, the reactionmixture is added to dilute sodium chloride solution, extracted threetimes with ethyl acetate, washed with thiosulfate solution, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. 479 mg of11β-[4-(2-iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-diol is obtainedas a crude product, which is used in the next stage without furtherpurification.

d)11β-{4-[2-(Methyl{3-](2-pyridylmethyl)sulfanyl]propyl}amino)-ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

470 mg of 11β-[4-(2-iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-dioland 554 mg of methyl{3-[(2-pyridylmethyl)sulfanyl]-propyl}amine aredissolved in 9 ml of N-methylpyrrolidone and stirred for 2 hours at 90°C. After the reaction solution is cooled to room temperature, the batchis added to semi-saturated sodium chloride solution, extracted threetimes with diethyl ether, the combined organic phases are washed withwater, dried on magnesium sulfate and concentrated by evaporation in avacuum. Preparative column chromatography on silica gel with methylenechloride/methanol as an eluant yields 93 mg of11β-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}amino)-ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=−31.8° (c=0.513 in chloroform).

EXAMPLE 1211β-{4-[2-(Methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}amino)-ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

68 mg of11β-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diolis dissolved in 2 ml of methanol and 0.12 ml of water, mixed with 28 mgof sodium metaperiodate and stirred for 16 hours at room temperature.For working-up, the reaction mixture is added to semi-saturated sodiumchloride solution, extracted three times with methylene chloride, washedwith saturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bymeans of preparative thin-layer chromatography with methylenechloride/methanol with the addition of ammonia as a mobile solvent. 31mg of11β-{4-[2-(methyl{3-[(2-pyridylmethyl)-sulfinyl]propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diolis obtained as a foam, [α]_(D) ²²=−33.3° (c=0.51 in chloroform).

EXAMPLE 1311β-{4-[2-(Methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

466 mg of 11β-[4-(2-iodoethyl)phenyl]estra-1,3,5(10)-triene-3,17β-dioland 359 mg of methyl{3-[4-(trifluoromethyl)benzyl-sulfanyl]propyl}amineare dissolved in 9 ml of N-methyl-pyrrolidone and stirred for 4 hours ata bath temperature of 40° C. After the reaction solution is cooled toroom temperature, the batch is added to semi-saturated sodium chloridesolution, extracted three times with diethyl ether, the combined organicphases are washed with saturated sodium chloride solution, dried onmagnesium sulfate and concentrated by evaporation in a vacuum.Preparative column chromatography on silica gel with methylenechloride/methanol as an eluant yields 256 mg of11β-{4-[2-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]propyl}-amino)ethyl]phenyl}-estra-1,3,5(10)-triene-3,17β-diolas a foam, [α]_(D) ²²=−20.2° (c=0.505 in chloroform).

EXAMPLE 1411β-{4-[2-(Methyl{3-[4-(trifluoromethyl)benzylsulfinyl]propyl}-amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17β-diol

100 mg of11β-{4-[2-(methyl{3-[4-(trifluoromethyl)benzyl-sulfanyl]propyl}amino)ethyl]-phenyl}estra-1,3,5(10)-triene-3,17β-diol is dissolved in 2.6 mlof methanol and 0.15 ml of water, mixed with 36 mg of sodiummetaperiodate, and stirred for 4 hours at room temperature. Forworking-up, the reaction mixture is added to semi-saturated sodiumchloride solution, extracted three times with methylene chloride, washedwith saturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bymeans of preparative thin-layer chromatography with methylenechloride/methanol with the addition of ammonia as a mobile solvent. 48mg of11β-{4-[2-(methyl{3-[4-(trifluoromethyl)-benzylsulfinyl]propyl}amino)ethyl]-phenyl}estra-1,3,5(10)-triene-3,17β-diolis obtained as a foam, [α]_(D) ²²=−28.8° (c=0.511 in chloroform).

Production of the Reagents3-[(4,4,5,5,5-Pentafluoropentyl)sulfanyl]propylamine

25 g of S-(4,4,5,5,5-pentafluoropentyl)thioacetate [Singh, S. M. et al.,Tet. Lett., (1994), 35, pp. 9141-9144] is introduced at 0° C. into 250ml of absolute acetonitrile and mixed drop by drop with 39.2 ml of a 30%sodium methylate solution. Stirring is continued for 15 minutes undercold conditions, before 23.2 g of 3-bromopropylamine hydrobromide isintroduced in portions. Then, it stirred for one more hour at 0° C. Thereaction mixture is then added to water, extracted three times withdiethyl ether, washed neutral, dried on magnesium sulfate andconcentrated by evaporation. After preparative column chromatography onsilica gel with methylene chloride/methanol with the addition of ammoniaas an eluant, 22.54 g of3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]propylamine is obtained.

Methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}amine

a) S-(2-pyridylmethyl)thioacetate

10.0 g of 2-(Chloromethyl)pyridine hydrochloride is introduced into 100ml of acetone, mixed with 14.0 g of potassium thioacetate and refluxedfor 2 hours at 80° C. For working-up, the reaction mixture is dilutedwith ethyl acetate and added to water. It is extracted three times withethyl acetate, the combined organic phases are washed with saturatedsodium bicarbonate solution and with saturated sodium chloride solution,dried on magnesium sulfate and concentrated by evaporation in a vacuum.After preparative column chromatography on silica gel with hexane/ethylacetate as an eluant, 9.78 g of S-(2-pyridylmethyl)thioacetate isobtained.

b) 2-[(3-Chloropropyl)sulfanylmethyl]pyridine

9.78 g of S-(2-pyridylmethyl)thioacetate in 90 ml of absolute methanolis mixed drop by drop with 10.9 ml of a 30% methanolic sodium methylatesolution while being cooled in an ice bath, and after the addition iscompleted, it is stirred for 20 more minutes. Then, 8.6 ml of1-bromo-3-chloropropane is added in drops at 4° C. and stirred for twomore hours under cold conditions and for one more hour at roomtemperature. Then, the reaction mixture is added to water, extractedthree times with ethyl acetate, the combined organic phases are washedwith saturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with hexane/ethyl acetate as an eluantyields 11.7 g of 2-[(3-chloropropyl)sulfanylmethyl]-pyridine.

c) Methyl{3-[(2pyridylmethyl)sulfanyl]propyl}amine

5.85 g of 2-[(3-chloropropyl)sulfanylmethyl]pyridine in 33.5 ml oftetrahydrofuran is mixed with 11.7 g of sodium iodide in a pressurevessel. Then, 17.05 g of methylamine is condensed at −20° C. and heatedovernight in a pressure vessel at a bath temperature of 50° C. After thereaction vessel was opened at −20° C., it is allowed to come toroom-temperature to allow excess methylamine to evaporate. The reactionsolution is added to dilute sodium chloride solution, extracted threetimes with methylene chloride, the combined organic phases are washedwith saturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. 5.7 g ofmethyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amine is obtained as a crudeproduct.

Methyl{3-[4-(trifluoromethyl)benzylsulfanyl]propyl}amine

a) 1-[(3-Bromopropyl)sulfanylmethyl]-4-(trifluoromethyl)benzene

25.0 g of 4-(trifluoromethyl)benzyl bromide is introduced into 84 ml ofacetonitrile, mixed with 8.3 ml of trimethylene sulfide and stirred for48 hours at room temperature. Then, the reaction mixture is evaporatedto the dry state and chromatographed on silica gel with hexane/methylenechloride. 29.47 of1-[(3-bromopropyl)sulfanyl-methyl]-4-(trifluoromethyl)benzene isobtained as an oil.

b) Methyl{3-[4-(trifluoromethyl)benzylsulfanyl]propyl}amine

18.8 g of methylamine is condensed at −20° C. in a solution of 10.0 g of1-[(3-bromopropyl)sulfanylmethyl]-4-(trifluoromethyl)-benzene in 37.0 mlof tetrahydrofuran, and it is stirred overnight at room temperature in apressure vessel. After the pressure vessel was opened at −20° C., it isallowed to come to room temperature to allow excess methylamine toevaporate. The reaction solution is added to dilute sodium chloridesolution, extracted three times with methylene chloride, the combinedorganic phases are washed with saturated sodium chloride solution, driedon magnesium sulfate and concentrated by evaporation in a vacuum. 8.32 gof methyl{3-[4-(trifluoromethyl)benzylsulfanyl]propyl}amine is obtainedas a crude product.

1-Bromo-4-[2-(tert-butyldimethylsilyloxy)ethyl]benzene

70 g of 2-(4-bromophenyl)ethanol is dissolved in 350 ml of absolutetetrahydrofuran and mixed with 4.97 g of imidazole. Then, 55 g oftert-butyldimethylsilyl chloride in 230 ml of absolute tetrahydrofuranis added in drops and stirred for 90 minutes at room temperature. Forworking-up, the reaction mixture is added to ice water, extracted threetimes with diethyl ether, washed with water, dried on magnesium sulfateand concentrated by evaporation in a vacuum. Preparative columnchromatography on silica gel with hexane/ethyl acetate as an eluantyields 111 g of 1-bromo-4-[2-(tort-butyldimethyl-silyloxy)ethyl]benzeneas a clear oil.

(S)-2-{[4-(Trifluoromethyl)phenyl]sulfanylmethyl}pyrrolidine

a)(S)-tert-Butyl-2-{[4-(trifluoromethyl)phenyl]sulfanylmethyl}-pyrrolidine-1-carboxylate

1.93 ml of a 30% sodium methylate solution is slowly added in drops at0° C. under inert gas to a solution that consists of 1.4 g of4-(trifluoromethyl)thiophenol in 15 ml of absolute acetone. After theaddition is completed, it is stirred for 30 more minutes under coldconditions, before 1.85 g of(S)-tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate[Katzenellenbogen, J. A. et al.; J. Med. Chem., (1994), 37, pp. 928-937]is added in drops to 5 ml of absolute acetone. Then, it is stirred for30 more minutes under cold conditions and for 12 hours at roomtemperature. For working-up, the reaction mixture is added to water,extracted three times with diethyl ether, washed twice with saturatedsodium chloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Preparative column chromatography on silica gelwith hexane/ethyl acetate as an eluant yields 1.8 g of(S)-tert-butyl-2-{[4-(trifluoromethyl)-phenyl]sulfanylmethyl}pyrrolidine-1-carboxylateas an oil.

b) (S)-2-{[4-(Trifluoromethyl)phenyl]sulfanylmethyl}pyrrolidine

920 mg of(S)-tert-butyl-2-{[4-(trifluoromethyl)phenyl)-sulfanylmethyl{pyrrolidine-1-carboxylateis added to a mixture, cooled to 0° C., that consists of 7.2 ml oftrifluoroacetic acid, 0.22 ml of triisopropylsilane and 0.30 ml ofwater, and it is stirred for 1 hour at 0° C. Then, the reaction is setat pH 10 with 10% potassium hydroxide solution, extracted three timeswith methylene chloride, washed with saturated sodium chloride solution,dried on magnesium sulfate and concentrated by evaporation in a vacuum.458 mg of (S)-2-{[4-(trifluoromethyl)-phenyl]sulfanylmethyl}-pyrrolidineis obtained as a crude product.

(S)-2-{[4-(Trifluoromethyl)phenyl]sulfinylmethyl}pyrrolidine

a)(S)-tert-Butyl-2-{[4-(trifluoromethyl)phenyl]sulfinylmethyl}-pyrrolidine-1-carboxylate

1.0 g of(S)-tert-butyl-2-{[4-(trifluoromethyl)phenyl]-sulfanylmethyl}pyrrolidine-1-carboxylateis dissolved in 48 ml of methanol and 2.6 ml of water, mixed with 833 mgof sodium metaperiodate and stirred for two days at room temperature andfor one hour at 50° C. For working-up, the reaction mixture is added tosemi-saturated sodium chloride solution, extracted three times withmethylene chloride, washed with saturated sodium chloride solution,dried on magnesium sulfate and concentrated by evaporation in a vacuum.The residue is purified by preparative column chromatography withhexane/acetone as an eluant. 929 mg of(S)-tert-butyl-2-β{[4-(trifluoromethyl)phenyl]-sulfinylmethyl}pyrrolidine-1-carboxylateis obtained.

b) (S)-2-{[4-(Trifluoromethyl)phenyl]sulfinylmethyl}pyrrolidine

920 mg of(S)-tert-butyl-2-{[4-(trifluoromethyl)phenyl]-sulfinyl-methyl}pyrrolidine-1-carboxylateis added to a mixture, cooled to 0° C., that consists of 7.2 ml oftrifluoroacetic acid, 0.22 ml of triisopropylsilane and 0.30 ml ofwater, heated for a short time to room temperature until the educt isdissolved and then stirred for 30 minutes at 0° C. Then, the reaction isset at pH 10 with lot potassium hydroxide solution, extracted threetimes with methylene chloride, washed with saturated sodium chloridesolution, dried on magnesium sulfate and concentrated by evaporation ina vacuum. 549 mg of(S)-2-{[4-(trifluoromethyl)-phenyl]sulfinyl}pyrrolidine is obtained as acrude product.

What is claimed is:
 1. An 11β-substituted estratriene of formula I

in which R³ means a hydrogen atom, a hydrocarbon radical with up to 8carbon atoms or a radical of partial formula R³—C(O)—, in which R³′means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atomsor a phenyl radical, R¹¹ means a radical of formula —A—B—Z—R²⁰, in whichA stands for a direct bond, and B stands for a straight-chain orbranched-chain alkylene, alkenylene or alkinylene group with 4, 5 or 6carbon atoms, Z stands for —NR²¹- and R²¹ stands for a C₁-C₃ alkylgroup, whereby R²⁰ means a hydrogen atom, a straight-chain orbranched-chain alkyl, alkenyl or alkinyl group with up to 10 carbonatoms, —D—C_(n)F_(2n+1), whereby D is a straight-chain or branched-chainalkylene, alkenylene or alkinylene group with up to 8 carbon atoms and nis an integer from 1 to 8, —D-aryl, whereby D has the already indicatedmeaning, and aryl stands for a phenyl, 1- or 2-naphthyl radical or aheteroaryl radical that is optionally substituted in one or two places,—L—CH═CF—C_(p)F_(2p+1), whereby L is a straight-chain or branched-chainalkylene, alkenylene or alkinylene group with up to 7 carbon atoms and pis an integer from 1 to 7, whereby in the three cases above in D or L, amethylene group can be replaced by a sulfur atom, a sulfone group or asulfoxide group, —D—O—(CH₂)q-aryl, whereby D and aryl have the alreadyindicated meanings, and q is 0, 1, 2 or 3, —D—O—(CH₂)_(r)—C_(n)F_(2n+1),whereby D and n have the already indicated meanings, and r stands for aninteger from 1 to 5, whereby in addition in all relevant cases above,R²¹ together with D with the inclusion of the nitrogen atom can thenform a pyrrolidine ring that is substituted in 2- or 3-position, or R²⁰and R²¹ with the nitrogen atom to which they are bonded form a saturatedor unsaturated heterocyclic compound with 5 or 6 chain links, whichoptionally contains one or two additional heteroatoms, selected fromnitrogen, oxygen and sulfur, and optionally is substituted, and R^(17a)in α- or β-position means a hydrogen atom, a C₁₋₅ alkyl, a C₂₋₅ alkenylor a C₂₋₅ alkinyl group or a trifluoromethyl group, or together with theradical OR^(17b) means a keto-oxygen atom, and R^(17b) means a hydrogenatom or a radical of partial formula R¹⁷′—C(O)—, in which R¹⁷′ means ahydrogen atom or a hydrocarbon radical with up to 8 carbon atoms.
 2. An11β-substituted estratriene according to claim 1, in which R³ is ahydrogen atom.
 3. An 11β-substituted estratriene according to claim 1,in which R³ is a benzoyl radical.
 4. An 11β-substituted estratrieneaccording to claim 1, in which R^(17b) is a hydrogen atom.
 5. An11β-substituted estratriene according to claim 1, in R¹¹ is selectedfrom the group of the following side chains—(CH₂)₅N(CH₃)—(CH₂)₃—S—(CH₂)₃C₂F₅, —(CH₂)₅NH—(CH₂)₃—S—(CH₂)₃C₂F₅,—(CH₂)₅N(CH₃)—(CH₂)₃—S—CH₂—2-Pyridyl,—(CH₂)₅N(CH₃)—(CH₂)₃—SO—CH₂—2-Pyridyl,—(CH₂)₅N(CH₃)—(CH₂)₃—S—CH₂-p-CF₃-Phenyl,—(CH₂)₅N(CH₃)—(CH₂)₃—SO—CH₂-p-CF₃-Phenyl,—(CH₂)₅-[2-pyrrolidine-1-yl]—CH₂—S-p-CF₃-Phenyl,—(CH₂)₅-[2-pyrrolidine-1-yl]—CH₂—SO-p-CF₃-Phenyl,—(CH₂)₅N(CH₃)(CH₂)₃C₂F₅, —(CH₂)₅N(CH₃)(CH₂)₆C₂F₅,—(CH₂)₅N(CH₃)(CH₂)₇C₂F₅, —(CH₂)₅N(CH₃)(CH₂)₈C₂F₅,—(CH₂)₆N(CH₃)(CH₂)₆C₂F₅, —(CH₂)₆N(CH₃)(CH₂)₇C₂F₅,—(CH₂)₆N(CH₃)(CH₂)₈C₂F₅, —(CH₂)₅N(CH₃)(CH₂)₂C₄F₉,—(CH₂)₅N(CH₃)(CH₂)₃C₆F₁₃, —(CH₂)₅N(CH₃)(CH₂)₃C₈F₁₇,—(CH₂)₅N(CH₃)(CH₂)₆C₄F₉, —(CH₂)₅N(CH₃)(CH₂)₆C₆F₁₃,—(CH₂)₅N(CH₃)(CH₂)₆C₈F₁₇, —(CH₂)₅N(CH₃)H, —(CH₂)₅N(CH₃)(CH₂)₉H,—(CH₂)₅N(CH₃)CH₂CH═CF—C₂F₅, —(CH₂)₅N(CH₃)CH₂CH═CF—C₃F₇,—(CH₂)₅N(CH₃)CH₂CH═CF—C₅F₁₁, —(CH₂)₅N(CH₃)CH₂CH═CF—C₇F₁₅,—(CH₂)₅-1-Pyrrolidinyl, —(CH₂)₅N(CH₃)(CH₂)₃OPhenyl,—(CH₂)₅N(CH₃)(CH₂)₃OBenzyl, —(CH₂)₅N(CH₃)(CH₂)₃O(CH₂)₃C₂F₅,—(CH₂)₅N(CH₃)(CH₂)₃CH(CH₃)₂, —(CH₂)₅N(CH₃)(CH₂)₃-Pyridyl,—(CH₂)₅N(CH₃)(CH₂)₃-Phenyl, —(CH₂)₅N(CH₃)(CH₂)₃-p-Tolyl,—(CH₂)₅N(CH₃)(CH₂)₃-p-ethoxyphenyl, —(CH₂)₅N(CH₃)(CH₂)₃-p-Tolyl,—(CH₂)₅N(CH₃)(CH₂)₃-p-Chlorophenyl, or —(CH₂)₅N(CH₃)(CH₂)₃—O—CH₂-Phenyl.6. A compound of claim 1 which is11β-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-(5-{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propylamino}pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-[5-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-(5-{methyl{3-[(2-pyridylmethyl)sulfonyl}propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-[5-(methyl{3-[4-trifluoromethyl)benzylsulfanyl]-propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-[5-(methyl{3-[4-(trifuoromethyl)benzylsulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfanyl-methyl}pyrrolidine-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfinyl-methyl}pyrrolidine-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(8,8,9,9,9-pentafluoro-nonyl)amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-nonyl-amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl{-estra-1,3,5(10)-triene-3,17β-diol,11β-β{6-[methyl-(8,8,9,9,9-pentafluoro-nonyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{6-[methyl-(9,9,10,10,10-pentafluoro-decyl)amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-[5-(methyl-amino)-pentyl]-estra-1,3,5(10)-triene-3,17β-diol,11β-(5-pyrrolidine-1-yl-pentyl)-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(4,4,5,5,5-pentafluoro-pentafluoro-pentyl)-amino}pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-undecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{6-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino)-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(3,4,4,5,5,6,6,7,7,8,8,8-dodecafluoro-oct-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino}-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5[methyl(3-phenoxy-propyl)-amino]pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[(3-benzyloxy-propyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-{N-methyl-N-3-(4,4,5,5,5-pentafluoropentyloxy)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-2-p-tolyl-ethyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-(5-{[2-(4-ethoxy-phenyl)-ethyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(3-phenyl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{-[methyl-(3-pyridin-3-yl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-{5-[methyl-(3-ptolyl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol,11β-(5-{[3-(4-chloro-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol,11β-(5-{[3-(4-ethoxy-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17β-diol,or11β{5[methyl-(4-methyl-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol.7. A pharmaceutical agent comprising a 11β-long-chain-substitutedestratriene according to claim
 1. 8. A pharmaceutical compositioncomprising at least one compound of formula I according to claim 1 and apharmaceutically compatible vehicle.
 9. An 11β-substituted estratrieneaccording to claim 1, wherein R_(17a) is a methyl, an ethenyl or anethynyl.
 10. An 11β-substituted estratriene according to claim 1,wherein R^(17a) is in the α-position.
 11. A method of providing anantiestrogenic action comprising administration an effective amount of acompound according to claim to a patient in need thereof.
 12. A methodof treating tumors comprising administrating an effective amount of acompound according to claim
 1. 13. A method of treating osteoporosis, orpre-, peri- or post-menopause comprising administrating an effectiveamount of a compound according to claim 1 to a patient in need thereof.14. A method of providing hormone replacement therapy comprisingadministering an effective amount of a compound according to claim 1 toa patient in need thereof.
 15. A method of treating breast cancer,endometrial cancer, prostate cancer, prostatic hyperplasia, anovulatoryinfertility, melanoma, male hair loss, diffuse alopecia, hirsutism,endometriosis, or endometrial carcinomas by administrating an effectiveamount of a compound according to claim 1 to a patient in need thereof.